Significant variation in human susceptibility to infections may be due in part to genetic heterogeneity within the host population. However, the genetic control of host resistance in immunocompetent individuals is polygenic and identification of polymorphic genes contributing to host resistance in human populations is a formidable task, because of epistatic gene interactions and the contribution of environmental factors. Animal models of human infections allow dissection of genetic factors contributing to host defense. Recently, we and others have identified several genetic loci controlling immunity to intracellular pathogens, some of which may control mechanisms of resistance that are common for several intracellular pathogens. Indeed, one of those loci (sst 1) controls both M. tuberculosis lung infection and systemic infections with F. tularensis and L. monocytogenes. We propose to study the genetic control of the early steps of pathogenesis caused by airborne infections with the two intracellular lung pathogens: M. tuberculosis and F. tularensis using mouse model. We will map genetic modifiers that counterbalance the detrimental effect of the sst 1 locus on lung tuberculosis and produce mouse strains congenic for those loci. We will establish an aerosol model of infection with a low dose of F. tularensis and determine which of the previously identified MTB-resistance loci are important in control of F. tularensis infection. We will test a panel of mouse inbred strains to find genetic variation in their ability to control early steps of disease caused by both pathogens and identify immunological correlates of host susceptibility using immunocompetent cells obtained from lung lesions. We will also test the role of host genetic variation in determining the efficiency of systemic vaccination against airborne infections with both pathogens. Understanding genetic risk factors for susceptibility to airborne infections should improve our ability to identify predisposed individuals and to develop optimal measures of protection and treatment in human populations.